Small molecule inhibitors of HIV proteases

ABSTRACT

Described herein are compounds, compositions, and methods for treating HIV and related diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/812,908, filed Jul. 14, 2010, which is the U.S. national application,filed under 35 U.S.C. §371(c), of international application No.PCT/US2009/031183, filed Jan. 16, 2009, which claims priority to U.S.Provisional Patent Application No. 61/021,702 filed Jan. 17, 2008, andU.S. Provisional Application Ser. No. 61/083,744, filed Jul. 25, 2008,the disclosures of which are incorporated herein by reference.

GOVERNMENT RIGHTS

This invention was made with government support under GM053386 awardedby the National Institutes of Health. The government has certain rightsin the invention.

BACKGROUND

The AIDS epidemic is one of the more challenging problems in medicine inthe 21st century (United Nations. 2004 Report on the global HIV/AIDSEpidemic: 4th global report. New York, U.S.A., 2004). The disclosure ofthe foregoing is incorporated herein in its entirety by reference. Inaddition, the entirety of the disclosures of each of the publicationscited herein are also incorporated herein by reference. A retrovirusdesignated human immunodeficiency virus (HIV) is the etiological agentof the complex disease that includes progressive destruction of theimmune system (acquired immune deficiency syndrome; AIDS) anddegeneration of the central and peripheral nervous system. This viruswas previously known as LAV, HTLV-III, or ARV. A common feature ofretrovirus replication is the extensive post-translational processing ofprecursor polyproteins by a vitally encoded protease to generate maturevital proteins required for virus assembly and function. Inhibition ofthis processing prevents the production of normally infectious virus.For example, Kohl, N. E. et al., Proc Nat'l Acad Sci 85:4686 (1988)demonstrated that genetic inactivation of the HIV encoded proteaseresulted in the production of immature, non-infectious virus particles.These results indicate that inhibition of the HIV protease represents aviable method for the treatment of AIDS and the prevention or treatmentof infection by HIV.

SUMMARY OF THE INVENTION

The invention described herein includes methods for treating HIV, AIDS,and AIDS-related diseases using the compounds described herein as wellas known compounds that heretofore have not been used or described asbeing useful in the treatment of such diseases. In addition, theinvention described herein includes compounds and compositions fortreating patients in need of relief from HIV, AIDS, and AIDS-relateddiseases.

The compounds described herein may be used in the treatment of HIV,AIDS, and AIDS-related diseases. Without being bound by theory, it issuggested that the compounds described herein may exert their utility bythe inhibition of proteases encoded by human immunodeficiency virus(HIV), such as HIV-1. The compounds or pharmaceutically acceptable saltsthereof, are of value in the prevention of infection by HIV, thetreatment of infection by HIV and the treatment of the resultingacquired immune deficiency syndrome (AIDS), either as compounds, thepharmaceutically acceptable salts, or pharmaceutical compositioningredients. It is appreciated that the compounds described herein maybe used alone or in combination with other compounds useful for treatingsuch diseases, including those compounds that may operate by the same ordifferent modes of action. Further, it is appreciated that the compoundsand compositions described herein may be administered alone or withother compounds and compositions, such as other antiviral agents,immunomodulators, antibiotics, vaccines, and the like.

In one illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula (I)

or pharmaceutically acceptable salts thereof; wherein,

X¹ is a bond, O, or an optionally substituted nitrogen; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, heterocycle, alkenyl, heteroalkyl,cycloheteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, or alkylheteroaryl, each of which is optionallysubstituted;

R² is selected from the group consisting of hydrogen, alkyl,heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, and a pro-drug moiety, each of which is optionallysubstituted;

R³ is hydrogen or alkyl;

W, X, Y, and Z are each independently selected from the group consistingof a bond, O, S, S(O), SO₂, optionally substituted nitrogen, optionallysubstituted phosphorus, P(O)R⁴, P(O)OR⁴, and (CR⁴R⁵)_(m), where m is 1to about 3, or Y and W and the attached atoms form an optionallysubstituted bicyclo-[3.2.1] ring system; providing that, when Z is Othen W and Y are not O or S and when Y is O then X and Z are not O or S;

R⁴ and R⁵ are, in each instance, independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, cycloheteroalkyl, alkenyl,alkoxy, optionally substituted amino, thioalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, nitrile, cyanoalkyl, carboxylicacid, or a derivative thereof, and alkylcarboxylic acid, or a derivativethereof, each of which is optionally substituted; and

Q is selected from the group consisting of —CH₂OR⁹, —CO₂R⁹, —CONR⁹R¹⁰,—C(O)SR⁹, —C(S)OR⁹, and —C(S)NR⁹R¹⁰; where R⁹ and R¹⁰ are eachindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, heteroalkyl, and arylalkyl; or one or both of R⁹ andR¹⁰ is a pro-drug moiety; or R⁹ and R¹⁰ together with the nitrogen towhich they are attached form an optionally substituted heterocycle.

In another illustrative embodiment, the methods described herein includecompounds, and pharmaceutical compositions containing such compounds ofthe following formula (II):

and pharmaceutically acceptable salts thereof; wherein,

r is an integer from 0 to 2;

X¹ is a bond, O, or NR¹⁴; and X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl,alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl, each ofwhich is optionally substituted;

R² and R¹⁴ are in each instance independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionallysubstituted arylalkoxy, optionally substituted amino, optionallysubstituted aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, and optionally substitutedheteroarylalkyl; either or both of R² and R¹⁴ is a pro-drug moiety;

R³ is hydrogen or alkyl;

W, X, Y, and Z are each independently selected from the group consistingof a bond, O, S, S(O), SO₂, NR⁴, PR⁴, P(O)R⁴, P(O)OR⁴, and (CR⁴R⁵)_(m),where m is 1 to about 3; providing that, when Z is O then W and Y arenot O or S and when Y is O then X and Z are not O or S;

R⁴ and R⁵ are, in each instance, independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxyl, optionallysubstituted amino, thioalkyl, heterocyclyl, heterocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, (CH₂)_(p)OR⁸, (CH₂)_(p)N(R⁸)₂, (CH₂)_(p)CN, and(CH₂)_(p)CO₂R⁸, where R⁸ in each occurrence is independently selectedfrom the group consisting of hydrogen, alkyl, optionally substitutedarylalkyl, and a pro-drug moiety, p is an integer from 0 to 5; and

Q is selected from the group consisting of —CH₂OR⁹, —CO₂R⁹, —CONR⁹R¹⁰,—C(O)SR⁹, —C(S)OR⁹, and —C(S)NR⁹R¹⁰; where R⁹ and R¹⁰ are eachindependently selected from the group consisting of hydrogen, alkyl,substituted alkyl, heteroalkyl, and arylalkyl; or one or both of R⁹ andR¹⁰ is a pro-drug moiety; or R⁹ and R¹⁰ together with the nitrogen towhich they are attached form an optionally substituted heterocycle.

In another illustrative embodiment, Q is CO₂R⁹ in each of formula (I)and/or (II). In another illustrative embodiment, R¹ is optionallysubstituted aryl in each of formula (I) and/or (II). In anotherillustrative embodiment, X¹ is O in each of formula (I) and/or (II). Inanother illustrative embodiment, X′ is a bond in each of formula (I)and/or (II). In another illustrative embodiment, X² is S(O)₂ in each offormula (I) and/or (II). In another illustrative embodiment, X² is C(O)in each of formula (I) and/or (II). In another illustrative embodiment,R² is H in each of formula (I) and/or (II). In another illustrativeembodiment, R³ is H in each of formula (I) and/or (II). In anotherillustrative embodiment, W, X, Y, and Z are taken together with theattached carbons to form a 5 to 8 membered heterocycle containing 1 or 2oxygen atoms, or 1 oxygen and 1 nitrogen atom, such as but not limitedto tetrahydrofuran, dioxolane, tetrahydropyran, dioxane, morpholine,oxepane, each of which is optionally substituted, in each of formula (I)and/or (II). In another illustrative embodiment, R⁴ and R⁵ are eachindependently selected from H, alkyl, CN, aryl, heteroaryl, heteroalkyl,such as ethers, amines, and the like, arylalkyl, arylheteroalkyl,heterocyclyl, each of which is optionally substituted, in each offormula (I) and/or (II). In another illustrative embodiment, one or moreof R⁴ and R⁵ is alkyl substituted with a carboxylic acid or derivativethereof in each of formula (I) and/or (II). It is to be understood thateach of the foregoing illustrative embodiments may be combined withothers in other embodiments of the invention described herein.Illustratively, in another embodiment, Q is CO₂R⁹, R¹ is optionallysubstituted aryl, X¹ is a bond, and X² is S(O)₂ in each of formula (I)and/or (II). Other combinations of the foregoing embodiments are alsodescribed herein.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula (III)

or pharmaceutically acceptable salts thereof; wherein,

X¹ is a bond, O, or an optionally substituted nitrogen; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, eachof which is optionally substituted;

R³ is hydrogen or alkyl;

each of R^(4a), R^(4b), and R^(4c), and each of R^(5a)R^(5ba), andR^(5c) are independently selected in each instance from the groupconsisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino,aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile,cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylicacid or a derivative thereof, each of which is optionally substituted;or any two of R^(4a), R^(4b), R^(4c), R^(5a)R^(5ba), and R^(5c)R⁴ and R⁵are taken together with the attached atoms to form a carbocycle orheterocycle; and

Q is a carboxylic acid or a derivative thereof.

In another illustrative embodiment, Q is CO₂R⁹ in each of formula (I),(II), and/or (III). In another illustrative embodiment, R¹ is optionallysubstituted aryl in each of formula (I), (II), and/or (III). In anotherillustrative embodiment, X¹ is O in each of formula (I), (II), and/or(III). In another illustrative embodiment, X′ is a bond in each offormula (I), (II), and/or (III). In another illustrative embodiment, X²is S(O)₂ in each of formula (I), (II), and/or (III). In anotherillustrative embodiment, X² is C(O) in each of formula (I), (II), and/or(III). In another illustrative embodiment, R³ is H in each of formula(I), (II), and/or (III). It is to be understood that each of theforegoing illustrative embodiments may be combined with others in otherembodiments of the invention described herein. Illustratively, inanother embodiment, Q is CO₂R⁹, R¹ is optionally substituted aryl, X¹ isa bond, and X² is S(O)₂ in each of formula (I), (II), and/or (III).Other combinations of the foregoing embodiments are also describedherein.

Without being bound by theory, it is suggested that in one aspect, thecompounds described herein, may be inhibiting proteases required foreffective viral replication by mimicking a transition state, such as thetetrahedral transition state of amide hydrolysis. Without being bound bytheory, it is suggested that in another aspect, the compounds describedherein, may be inhibiting or interfering with viral replication byinhibiting dimerization of the protease.

DETAILED DESCRIPTION

In one illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula

and pharmaceutically acceptable salts thereof; wherein,

X¹ is a bond, O, or an optionally substituted nitrogen; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, eachof which is optionally substituted;

R² is selected from the group consisting of hydrogen, alkyl,heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, alkylthio,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, and pro-drug moieties, each of which is optionallysubstituted;

R³ is hydrogen or alkyl;

X, Y, and Z are taken together with the attached atoms to form aheterocycle or heterobicycle, each of which is optionally substituted;

R⁴ and R⁵ are, in each instance, independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino,aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile,cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylicacid or a derivative thereof, each of which is optionally substituted;or R⁴ and R⁵ are taken together with the attached atoms to form acarbocycle or heterocycle; and

Q is selected from the group consisting of heteroalkyl, hydroxyalkyl,and carboxylic acid or a derivative thereof.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula

and pharmaceutically acceptable salts thereof; wherein,

X¹ is a bond, O, or an optionally substituted nitrogen; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, eachof which is optionally substituted;

R³ is hydrogen or alkyl;

each of R^(4a), R^(4b), and R^(4c), and each of R^(5a)R^(5ba), andR^(5c) are independently selected in each instance from the groupconsisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino,aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile,cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylicacid or a derivative thereof, each of which is optionally substituted;or any two of R^(4a), R^(4b), R^(4c), R^(5a)R^(5ba), and R^(5c)R⁴ and R⁵are taken together with the attached atoms to form a carbocycle orheterocycle; and

Q is a carboxylic acid or a derivative thereof.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein Z is selected from thegroup consisting of a bond, S(O), SO₂, optionally substituted nitrogen,and (CR⁴R⁵)_(m), where m is 1 to about 3. In another illustrativeembodiment, the methods described herein include compounds andpharmaceutical compositions wherein X and Y are each independentlyselected from the group consisting of a bond, O, S, S(O), SO₂,optionally substituted nitrogen, and (CR⁴R⁵)_(m), where m is 1 to about3; providing that, when X is O then Y is not O or S and when Y is O thenX is not O or S. In another illustrative embodiment, the methodsdescribed herein include compounds and pharmaceutical compositionswherein W, X, Y, and Z are taken together with the attached carbons toform a 5 to 8 membered heterocycle containing 1 or 2 oxygen atoms. Inanother illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein W, X, Y, and Z aretaken together with the attached carbons to form a 5 to 8 memberedheterocycle containing 1 oxygen and 1 nitrogen atom. In anotherillustrative embodiment, the methods described herein include compoundsand pharmaceutical compositions wherein the heterocycle is atetrahydrofuran, dioxolane, tetrahydropyran, dioxane, morpholine,oxepane, each of which is optionally substituted.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein the heterobicycle is aoxabicyclo-[3.2.1]-octane, which is optionally substituted. In anotherembodiment, the optionally substituted oxabicyclo-[3.2.1]-octane issubstituted with an optionally substituted fused phenyl.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein one of X, Y, or Z is Oor NR^(2a), where R^(2a) is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino,alkylthio, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, and pro-drug moieties, each of which is optionallysubstituted; and the others of X, Y, and Z are selected from the groupconsisting of a bond and (CR⁴R⁵)_(m), where m is 1 to about 3.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X is O; and Y and Zare each (CR⁴R⁵)_(m), where m is 1 to about 3; and Z is a bond. Inanother illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein Y is O; and X and Zare each (CR⁴R⁵)_(m), where m is 1 to about 3. In another illustrativeembodiment, the methods described herein include compounds andpharmaceutical compositions wherein one of X is O; Y is a bond, and Z is(CR⁴R⁵)_(m), where m is 1 to about 3. In another illustrativeembodiment, the methods described herein include compounds andpharmaceutical compositions wherein each of X, Y, and Z is (CR⁴R⁵)_(m),where m is 1. In another illustrative embodiment, the methods describedherein include compounds and pharmaceutical compositions wherein each ofX and Y is (CR⁴R⁵)_(m), where m is 1; and Z is a bond.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein Q is selected from thegroup consisting of —CH₂OR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —C(O)SR⁹, —C(S)OR⁹, and—C(S)NR⁹R¹⁰; where R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or one or both of R⁹ and R¹⁰ is a pro-drug moiety; or R⁹ andR¹⁰ together with the nitrogen to which they are attached form anoptionally substituted heterocycle. In another illustrative embodiment,the methods described herein include compounds and pharmaceuticalcompositions wherein Q is CO₂R⁹.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein R¹ is optionallysubstituted aryl.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X¹ is O and X² isC(O). In another illustrative embodiment, the methods described hereininclude compounds and pharmaceutical compositions wherein X is a bond.In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X² is S(O)₂. Inanother illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X¹ is a bond and X² isS(O)₂. In another illustrative embodiment, the methods described hereininclude compounds and pharmaceutical compositions wherein X¹ is O. Inanother illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X² is C(O).

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein R² is H. In anotherillustrative embodiment, the methods described herein include compoundsand pharmaceutical compositions wherein R³ is H. In another illustrativeembodiment, the methods described herein include compounds andpharmaceutical compositions wherein R⁴ and R⁵ are each independentlyselected from H, alkyl, CN, aryl, heteroaryl, heteroalkyl, such asethers, amines, and the like, arylalkyl, arylheteroalkyl, heterocyclyl,each of which is optionally substituted. In another illustrativeembodiment, the methods described herein include compounds andpharmaceutical compositions wherein one or more of R⁴ and R⁵ is alkylsubstituted with a carboxylic acid or derivative thereof.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein Q is CO₂R⁹, R¹ isoptionally substituted aryl, X¹ is a bond, and X² is S(O)₂.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions of the formula

and pharmaceutically acceptable salts thereof; wherein

R⁵ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, cycloheteroalkyl, alkenyl, alkoxy, optionally substitutedamino, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,nitrile, cyanoalkyl, carboxylic acid, or a derivative thereof, andalkylcarboxylic acid, or a derivative thereof, each of which isoptionally substituted;

R⁷ is selected from the group consisting of hydrogen, hydroxy, alkoxyoptionally substituted alkyl, heteroalkyl, optionally substitutedalkylaryl, optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, and NR⁹R¹⁰,where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocyclyl; and

R⁸ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, and alkylheteroaryl, each of which is optionallysubstituted;

R¹¹ is hydrogen, alkyl, arylalkyl or pro-drug moiety.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula

and pharmaceutically acceptable salts thereof; wherein

X¹ is a bond, optionally substituted nitrogen or O;

R² is selected from the group consisting of hydrogen, alkyl,heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, and a pro-drug moiety, each of which is optionallysubstituted;

R⁵ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, cycloheteroalkyl, alkenyl, alkoxy, optionally substitutedamino, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,nitrile, cyanoalkyl, carboxylic acid, or a derivative thereof, andalkylcarboxylic acid, or a derivative thereof, each of which isoptionally substituted;

R⁷ is hydrogen, alkyl, alkenyl, heteroalkyl, alkylaryl, arylalkyl,alkylheteroaryl, heteroarylalkyl, alkoxy or NR⁹R¹⁰, each of which isoptionally substituted, where R⁹ and R¹⁰ are each independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,heteroalkyl, and arylalkyl; or R⁹ and R¹⁰ together with the nitrogen towhich they are attached form an optionally substituted heterocycle; and

R⁸ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, and alkylheteroaryl, each of which is optionallysubstituted; and

R¹¹ is selected from the group consisting of hydrogen, alkyl, arylalkyl,and pro-drug moiety.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein R⁸ is aryl. In anotherillustrative embodiment, the methods described herein include compoundsand pharmaceutical compositions wherein R⁸ is naphthyl, quinolinyl orphenyl, each of which is optionally substituted.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions of the formula

and pharmaceutically acceptable salts thereof; wherein

R¹ is optionally substituted aryl; R² is selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, arylalkoxy,amino, aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, and a pro-drug moiety, each ofwhich is optionally substituted;

R⁵ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, cycloheteroalkyl, alkenyl, alkoxy, optionally substitutedamino, thioalkyl, heterocyclyl, heterocyclyl alkyl, aryl, heteroaryl,arylalkyl, heteroarylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,nitrile, cyanoalkyl, carboxylic acid, or a derivative thereof, andalkylcarboxylic acid, or a derivative thereof, each of which isoptionally substituted;

R⁷ is hydrogen, alkyl, alkenyl, heteroalkyl, alkylaryl, arylalkyl,alkylheteroaryl, heteroarylalkyl, alkoxy or NR⁹R¹⁰, each of which isoptionally substituted, where R⁹ and R¹⁰ are each independently selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,heteroalkyl, and arylalkyl; or R⁹ and R¹⁰ together with the nitrogen towhich they are attached form an optionally substituted heterocycle;

R¹² and R¹¹ are each independently selected from the group consisting ofhydrogen, alkyl, arylalkyl and pro-drug moiety; and

R¹³ is from one to three substituents, each independently selected fromthe group consisting of hydrogen, alkyl, haloalkyl, heteroalkyl,halogen, arylalkyl, optionally substituted amino, alkoxyl,alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio,nitro, C(O)OR⁹ and C(O)NR⁹R¹⁰.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula

and pharmaceutically acceptable salts thereof; wherein

R⁷ is independently selected in each instance from hydrogen, optionallysubstituted alkyl, heteroalkyl, optionally substituted alkylaryl,optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹ or NR⁹R¹⁰,where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; and R^(9a) ishydrogen, alkyl, arylalkyl or pro-drug.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of theabove wherein R′ aryl or heteroaryl, each of which is optionallysubstituted.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of theabove formula wherein X¹ is a bond, O, or NR¹⁴; X² is CO or SO₂; R¹ isalkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl,heteroaryl, heteroarylalkyl, or alkylheteroaryl, each of which isoptionally substituted; R² is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionally substitutedarylalkoxy, optionally substituted amino, optionally substitutedaminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl, and apro-drug moiety; and R⁴ is aryl or heteroaryl, each of which isoptionally substituted;

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of theabove formula wherein X¹ is a bond, O, or NR¹⁴; X² is CO or SO₂; and R¹is alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl,heteroaryl, heteroarylalkyl, or alkylheteroaryl, each of which isoptionally substituted; R² is hydrogen; R¹⁴ is selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionallysubstituted arylalkoxy, optionally substituted amino, optionallysubstituted aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, and a pro-drug moiety.

In another illustrative embodiment, the compounds of following formulaare described

and pharmaceutically acceptable salts thereof; wherein

R¹ is optionally substituted aryl; R² is hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, or a pro-drug moiety;

R⁴ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, and alkylheteroaryl; R⁵ is selected from the groupconsisting of hydrogen, nitrile, alkyl, cycloalkyl, heterocyclyl,alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl,alkylheteroaryl, (CH₂)p-OR⁸, (CH₂)p-CO₂R⁸, and (CH₂)p-NHR⁸, where p isan integer from 0 to 5, and R⁸ in each instance is independentlyselected from the group consisting of hydrogen, alkyl, optionallysubstituted arylalkyl, and pro-drug moiety; R⁷ is hydrogen, optionallysubstituted alkyl, heteroalkyl, optionally substituted alkylaryl,optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹ or NR⁹R¹⁰,where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; and R¹¹ ishydrogen, alkyl, arylalkyl or pro-drug moiety.

In another illustrative embodiment, the compounds of the followingformula are described:

and pharmaceutically acceptable salts thereof; wherein

R¹ is alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl,alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl, each ofwhich is optionally substituted;

R² and R⁴ are each independently selected in each instance from thegroup consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl,aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, andalkylheteroaryl; R⁵ is selected from the group consisting of hydrogen,nitrile, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl,alkylaryl, heteroaryl, heteroarylalkyl; Q is an alcohol or a derivativethereof.

In another illustrative embodiment, the compounds of following formulaare described

and pharmaceutically acceptable salts thereof; wherein

R¹ is optionally substituted aryl;

X¹ is a bond, NR¹⁴ or O; R² and R¹⁴ are in each instance independentlyselected from the group consisting of hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, and a pro-drug moiety;

R⁴ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, and alkylheteroaryl;

R⁵ is selected from the group consisting of hydrogen, nitrile, alkyl,cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl,heteroaryl, heteroarylalkyl, alkylheteroaryl, (CH₂)p-OR⁸, (CH₂)p-CO₂R⁸,and (CH₂)p-NHR⁸, where p is an integer from 0 to 5, and R⁸ in eachinstance is independently selected from the group consisting ofhydrogen, alkyl, optionally substituted arylalkyl, and pro-drug moiety,with the proviso that at least one of R⁴ or R⁵ is not hydrogen;

R⁷ is independently selected in each instance from hydrogen, optionallysubstituted alkyl, heteroalkyl, optionally substituted alkylaryl,optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹ or NR⁹R¹⁰,where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; and R¹¹ ishydrogen, alkyl, arylalkyl or pro-drug moiety.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein R⁵ is allyl orhydrogen.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions of the formula

and pharmaceutically acceptable salts thereof; wherein

R^(a) represents from 0 to 3 substituents independently selected in eachinstance from hydroxy, alkyl, heteroalkyl, alkoxy, aryl, arylalkyl,hydroxy, optionally substituted amino, and thioalkyl, each of which isoptionally substituted, or two vicinal R^(a) together with the attachedcarbons form a fused ring.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X² is SO₂; X¹ is abond; R³ is hydrogen; R¹ is aryl; and Q is a carboxylic acid or aderivative thereof.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions of the formula

and pharmaceutically acceptable salts thereof; wherein

X¹ is a bond, O, or an optionally substituted nitrogen; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, eachof which is optionally substituted;

R³ is hydrogen or alkyl;

each of R^(4a), R^(4b), and R^(4c), and each of R^(5a)R^(5ba), andR^(5c) are independently selected in each instance from the groupconsisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino,aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile,cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylicacid or a derivative thereof, each of which is optionally substituted;or any two of R^(4a), R^(4b), R^(4c), R^(5a)R^(5ba) and R^(5c)R⁴ and R⁵are taken together with the attached atoms to form a carbocycle orheterocycle; and

Q is a carboxylic acid or a derivative thereof.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein Q is selected from thegroup consisting of —CH₂OR⁹, —CO₂R⁹, —CONR⁹R¹⁰, —C(O)SR⁹, —C(S)OR⁹, and—C(S)NR⁹R¹⁰; where R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or one or both of R⁹ and R¹⁰ is a pro-drug moiety; or R⁹ andR¹⁰ together with the nitrogen to which they are attached form anoptionally substituted heterocycle. In another illustrative embodiment,the methods described herein include compounds and pharmaceuticalcompositions wherein Q is CO₂R⁹.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein R¹ is optionallysubstituted aryl. In another illustrative embodiment, the methodsdescribed herein include compounds and pharmaceutical compositionswherein R¹ is substituted phenyl. In another illustrative embodiment,the methods described herein include compounds and pharmaceuticalcompositions wherein R¹ is optionally substituted aryl.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X¹ is O and X² isC(O). In another illustrative embodiment, the methods described hereininclude compounds and pharmaceutical compositions wherein X¹ is a bond.In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X² is S(O)₂. Inanother illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X¹ is a bond and X² isS(O)₂. In another illustrative embodiment, the methods described hereininclude compounds and pharmaceutical compositions wherein X¹ is O. Inanother illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein X² is C(O).

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions wherein R³ is H.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula

and pharmaceutically acceptable salts thereof; wherein

X¹ is a bond, O, or an optionally substituted nitrogen; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, alkenyl, heteroalkyl, heterocyclyl,heterocyclylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, eachof which is optionally substituted;

R² is selected from the group consisting of hydrogen, alkyl,heteroalkyl, hydroxy, alkoxy, arylalkoxy, amino, alkylthio,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, and pro-drug moieties, each of which is optionallysubstituted;

R³ is hydrogen or alkyl;

X, Y, and Z are taken together with the attached atoms to form aheterocycle or heterobicycle, each of which is optionally substituted;

R⁴ and R⁵ are, in each instance, independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, alkenyl, alkoxy, amino,aminoalkyl, thioalkyl, heterocyclyl, heterocyclylalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, hydroxyalkyl, nitrile,cyanoalkyl, carboxylic acid or a derivative thereof, and alkylcarboxylicacid or a derivative thereof, each of which is optionally substituted;or R⁴ and R⁵ are taken together with the attached atoms to form acarbocycle or heterocycle; and

Q is selected from the group consisting of heteroalkyl, hydroxyalkyl,and carboxylic acid or a derivative thereof;

providing that the compound is not a compound of the formulae

wherein R⁵ is hydrogen, cyano or CH₂CH═CH₂; n is 1 or 2; R^(x) is1-naphthyl or phenyl; and R^(y) is tosyl or hydrogen.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of thefollowing formula

and pharmaceutically acceptable salts thereof; wherein

X¹ is a bond, O, or NR¹⁴; X² is CO or SO₂;

R¹ is alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl,alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl, each ofwhich is optionally substituted;

R² and R¹⁴ are in each instance independently selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionallysubstituted arylalkoxy, optionally substituted amino, optionallysubstituted aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, and a pro-drug moiety;

R⁴ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, and alkylheteroaryl;

R⁵ is selected from the group consisting of hydrogen, nitrile, alkyl,cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl,heteroaryl, heteroarylalkyl, alkylheteroaryl, (CH₂)p-OR⁸, (CH₂)p-CO₂R⁸,and (CH₂)p-NHR⁸, where p is an integer from 0 to 5, and R⁸ in eachinstance is independently selected from the group consisting ofhydrogen, alkyl, optionally substituted arylalkyl, and pro-drug moiety;

R⁷ is hydrogen, optionally substituted alkyl, heteroalkyl, optionallysubstituted alkylaryl, optionally substituted arylalkyl, optionallysubstituted alkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹or NR⁹R¹⁰, where R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; and R^(9a) ishydrogen, alkyl, arylalkyl or pro-drug

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of theabove wherein R¹ aryl or heteroaryl, each of which is optionallysubstituted.

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of theabove formula wherein X¹ is a bond, O, or NR¹⁴; X² is CO or SO₂; R¹ isalkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl,heteroaryl, heteroarylalkyl, or alkylheteroaryl, each of which isoptionally substituted; R² is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionally substitutedarylalkoxy, optionally substituted amino, optionally substitutedaminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl, and apro-drug moiety; and R⁴ is aryl or heteroaryl, each of which isoptionally substituted;

In another illustrative embodiment, the methods described herein includecompounds and pharmaceutical compositions comprising compounds of theabove formula wherein X¹ is a bond, O, or NR¹⁴; X² is CO or SO₂; and R¹is alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl,heteroaryl, heteroarylalkyl, or alkylheteroaryl, each of which isoptionally substituted; R² is hydrogen; R¹⁴ is selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionallysubstituted arylalkoxy, optionally substituted amino, optionallysubstituted aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, and a pro-drug moiety.

In another illustrative embodiment, the compounds of following formulaare described;

wherein R¹ is optionally substituted aryl; R² is hydrogen, alkyl,heteroalkyl, hydroxy, alkoxy, optionally substituted arylalkoxy,optionally substituted amino, optionally substituted aminoalkyl,alkylthio, heterocyclyl, heterocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted arylalkyl,optionally substituted heteroarylalkyl, or a pro-drug moiety;

R⁴ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, arylalkyl, alkylaryl, heteroaryl,heteroarylalkyl, and alkylheteroaryl; R⁵ is selected from the groupconsisting of hydrogen, nitrite, alkyl, cycloalkyl, heterocyclyl,alkenyl, aryl, aryl alkyl, alkylaryl, heteroaryl, heteroarylalkyl,alkylheteroaryl, (CH₂)p-OR⁸, (CH₂)p-CO₂R⁸, and (CH₂)p-NHR⁸, where p isan integer from 0 to 5, and R⁸ in each instance is independentlyselected from the group consisting of hydrogen, alkyl, optionallysubstituted arylalkyl, and pro-drug moiety; R⁷ is hydrogen, optionallysubstituted alkyl, heteroalkyl, optionally substituted alkylaryl,optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹ or NR⁹R¹⁰,where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; and R¹¹ ishydrogen, alkyl, arylalkyl or pro-drug moiety.

In another illustrative embodiment, the compounds of the followingformula are described:

wherein R¹ is alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl,alkylaryl, heteroaryl, heteroarylalkyl, or alkylheteroaryl, each ofwhich is optionally substituted;

R² and R⁴ are each independently selected in each instance from thegroup consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl,aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, andalkylheteroaryl; R⁵ is selected from the group consisting of hydrogen,nitrile, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, arylalkyl,alkylaryl, heteroaryl, heteroarylalkyl; Q is an alcohol or a derivativethereof.

In another illustrative embodiment, the compounds of following formulaare described;

wherein R¹ is optionally substituted aryl;

X¹ is a bond, NR¹⁴ or O; R² and R¹⁴ are in each instance independentlyselected from the group consisting of hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, and a pro-drug moiety;

R¹ is optionally substituted aryl;

X¹ is a bond, NR¹⁴ or O; R² and R¹⁴ are in each instance independentlyselected from the group consisting of hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, and a pro-drug moiety;

R⁷ is hydrogen, optionally substituted alkyl, heteroalkyl, optionallysubstituted alkylaryl, optionally substituted aryl alkyl, optionallysubstituted alkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹or NR⁹R¹⁰, where R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; and R¹¹ ishydrogen, alkyl, arylalkyl or pro-drug moiety.

As used herein the term amino generally refers to primary, secondary,and tertiary amino groups, including but not limited to NH2, alkylamino,dialkylamino, arylalkylamino, and the like.

As used herein the term carboxylic acid derivative generally refers toesters, amides, including primary, secondary, and tertiary amides, acylhydrazides, hydroxamic acids and esters, cyano, and the like.

As used herein the term heteroalkyl generally refers to straight-chainor branched alkyl groups where one or more carbon atoms are replaced bya heteroatom, such as oxygen, nitrogen, sulfur, and the like, andincludes but is not limited to alkoxyalkyl, alkylaminoalkyl,alkylaminoalkyloxyalkyl, alkylthioalkyl, and the like.

As used herein the term substituted when applied to aryl, heteroaryl,and the like generally refers to halo, alkyl, alkoxy, heteroalkyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl, hydroxy, amino, alkyl and arylsulfonyl, sulfonamide, and the like]

As used herein the term substituted when applied to alkyl, heteroalkyl,cycloalkyl, and the like generally refers to halo, alkyl, alkoxy,heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, hydroxy,amino, alkyl and aryl sulfonyl, sulfonamide, and the like]

In another embodiment, optional substituents in each of the foregoinginclude those found on optionally substituted aryl and heteroarylinclude one or more groups selected from alkyl, alkoxy, amino, which maybe mono or dialkylated, or acylated, aryl, arylalkyl, halo, heteroalkyl,heteroalkoxy, cyano, nitro, and the like. In one embodiment, heteroalkylincludes alkoxylalkyl, aminoalkyl, where the amino group may be mono ordialkylated, or acylated, haloalkyl, haloalkoxyalkyl, and the like.

The above formula includes compounds that are described in Ghosh et al.(Organic Letters 7:7-10 (2005)), the entirety of the disclosure of whichis incorporated herein by reference. Ghosh et al. also describedsuitable methods for preparing the compounds described herein. As such,the compounds described in Ghosh et al. are not included in the novelcompounds described herein. However, the compounds of Ghosh et al. areincluded in the methods described herein for treating HIV, AIDS, andrelated diseases and disease states.

In one embodiment of the compounds described herein, the followingcompounds are not included:

where Ts=tosyl, Ph=phenyl, Np=naphthyl, and R═H, CN, or allyl. In oneillustrative embodiment of the methods described herein, one or more ofthe foregoing compounds is included in the pharmaceutical compositionsor used in the methods described herein, including the correspondingcarboxylic acids and derivatives thereof, including thiocarboxylic acidsand esters, thionocarboxylic acids and esters, amides, thioamides, andthe like.

In another illustrative embodiment, the compounds of the followingformula are described:

wherein R is alkyl, including methyl, amino, or alkoxy, includingmethoxy.

In another illustrative embodiment, the compounds of the followingformula are described:

wherein R=alkyl; R⁴=Ph, Ar, alkyl, heteroalkyl or heteroaryl group, and

R⁵=alkyl, including Me;

R=alkoxy, including methoxy; R⁴=Ph, Ar, alkyl, heteroalkyl andheteroaryl group, and

R⁵=alkyl, including Me; R⁴=Ph, Ar, alkyl, heteroalkyl and heteroarylgroup;

R═NH₂; R⁴=Ph, Ar, alkyl, heteroalkyl and heteroaryl group, and

R⁵=alkyl, including Me; R⁴=Ph, Ar, alkyl, heteroalkyl and heteroarylgroup; or

R═R⁴=Ph, Ar, alkyl, heteroalkyl and heteroaryl group, and

R⁵=alkyl, including Me; R⁴=Ph, Ar, alkyl, heteroalkyl and heteroarylgroup.

In another illustrative embodiment, the compounds of the followingformulae are described:

where Ts is a tosyl group (4-Me-PhSO₂).

In another illustrative embodiment, the compounds of the followingformula are described:

wherein R=hydrogen or alkyl; R¹=hydrogen, Ph, Ar, alkyl, heteroalkyl orheteroaryl group, and R²=alkyl, including Me; R¹=Ph, Ar, alkyl,heteroalkyl and heteroaryl group; or

R=alkoxy, including methoxy; and R²=alkyl, including Me; R¹=Ph, Ar,alkyl, heteroalkyl and heteroaryl group; or

R═NH₂; R¹=Ph, Ar, alkyl, heteroalkyl and heteroaryl group, and R²=alkyl,including Me; or

R═R¹=Ph, Ar, alkyl, heteroalkyl and heteroaryl group, and R²=alkyl,including Me; R¹=Ph, Ar, alkyl, heteroalkyl and heteroaryl group.

In another illustrative embodiment, the compounds of the followingformulae are described:

In another illustrative embodiment, the compounds of the followingformula are described:

wherein, for example, R═H, CN, (CH₂)p-OR⁸, (CH₂)p-CO₂R⁸, (CH₂)p-NHR⁸,and the like; p is an integer from 0 to 5; where R⁸ in each occurrenceis independently selected from hydrogen, alkyl, and optionallysubstituted arylalkyl, or one or more R⁸ is a pro-drug moiety.

In another illustrative embodiment, the compounds of the followingformula are described:

wherein, for example, R═H, CN, (CH₂)p-OR⁸, (CH₂)p-CO₂R⁸, (CH₂)p-NHR⁸,and the like, where p is an integer from 0 to 5; and R⁸ in eachoccurrence is independently selected from H, alkyl, and optionallysubstituted arylalkyl, or one or more R⁸ is a pro-drug moiety.

In another illustrative embodiment, the compounds of the followingformulae are described:

wherein X is selected from O, S, S(O), SO₂, NR⁴, PR⁴, P(O)R⁴, P(O)OR⁴,and C(R⁴R⁵); and is illustratively O.

Ar=Ph, or substituted phenyl, such as, but not limited to alkoxyphenyl,including p-, m-, and o-anisolyl, 3,4-benzodioxanyl,3,4-benzodioxolanyl, and the like;

R¹═H, alkyl, NH₂, alkoxy, CH₂OH;

R²═H, CH₂CHMe₂, (CH₂)₂CHMe₂; and

R═OH, OR⁸, NHR⁸, wherein each occurrence is independently selected fromH, alkyl, such as, but not limited to, methyl and ethyl, and optionallysubstituted arylalkyl including, but not limited to, benzyl, or one ormore R⁸ is a pro-drug moiety.

In another illustrative embodiment, the compounds of the followingformulae are described;

In another illustrative embodiment, the compounds of following formulaeare described;

In another illustrative embodiment, the compounds of the followingformulae are described;

In another illustrative embodiment, the compounds of the followingformula are described:

R¹ is optionally substituted aryl; R² is hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, or a pro-drug moiety; R⁵ is selected fromthe group consisting of hydrogen, nitrile, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, alkylaryl, arylalkyl, heteroaryl,heteroarylalkyl, and alkylheteroaryl; R⁷ is hydrogen, optionallysubstituted alkyl, heteroalkyl, optionally substituted alkylaryl,optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹ or NR⁹R¹⁰;where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; R¹² and R¹¹ areeach independently selected from the group consisting of hydrogen,alkyl, arylalkyl and pro-drug moiety; and R¹³ is from one to threesubstituents independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, heteroalkyl, halogen, arylalkyl, optionallysubstituted amino, alkoxyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,arylsulfinyl, alkylthio, nitro, C(O)OR⁹ and C(O)NR⁹R¹⁰.

In another illustrative embodiment, the compounds of the followingformula are described:

In another illustrative embodiment, the compounds of the followingformula are described:

R¹ is optionally substituted aryl; R² is hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclyl alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted arylalkyl,optionally substituted heteroarylalkyl, or a pro-drug moiety; R⁵ isselected from the group consisting of hydrogen, nitrile, alkyl,cycloalkyl, heterocyclyl, alkenyl, aryl, alkylaryl, arylalkyl,heteroaryl, heteroarylalkyl, and alkylheteroaryl; R⁷ is hydrogen,optionally substituted alkyl, heteroalkyl, optionally substitutedalkylaryl, optionally substituted arylalkyl, optionally substitutedalkylheteroaryl, optionally substituted heteroarylalkyl, OR⁹ or NR⁹R¹⁰;where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; or R⁹ and R¹⁰ together with the nitrogen to which they areattached form an optionally substituted heterocycle; R¹² and R¹¹ areeach independently selected from the group consisting of hydrogen,alkyl, arylalkyl and pro-drug moiety; and R¹³ is hydroxyl or OR⁹.

In another illustrative embodiment, the compounds of the followingformula are described:

R¹ is optionally substituted aryl; R² is hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, or a pro-drug moiety; and R⁵ is selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl,alkenyl, aryl, alkylaryl, arylalkyl, heteroaryl, heteroarylalkyl, andalkylheteroaryl.

In another illustrative embodiment, the compounds of the followingformula are described:

R¹ is optionally substituted aryl; R² is hydrogen, alkyl, heteroalkyl,hydroxy, alkoxy, optionally substituted arylalkoxy, optionallysubstituted amino, optionally substituted aminoalkyl, alkylthio,heterocyclyl, heterocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted arylalkyl, optionallysubstituted heteroarylalkyl, or a pro-drug moiety; R⁵ is selected fromthe group consisting of hydrogen, nitrile, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, alkylaryl, arylalkyl, heteroaryl,heteroarylalkyl, and alkylheteroaryl; R⁹ is selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl; R¹² and R¹¹ are each independently selected from the groupconsisting of hydrogen, alkyl, arylalkyl and pro-drug moiety.

In another illustrative embodiment, the compounds of the followingformula are described

R⁵ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,heterocyclyl, alkenyl, aryl, alkylaryl, arylalkyl, heteroaryl,heteroarylalkyl, and alkylheteroaryl; and X is hydroxyl or amino.

In another illustrative embodiment, the compounds of the followingformula are described

X is hydroxyl or amino.

In another illustrative embodiment, the compounds of the followingformula are described:

R² is hydrogen, alkyl, heteroalkyl, hydroxy, alkoxy, optionallysubstituted arylalkoxy, optionally substituted amino, optionallysubstituted aminoalkyl, alkylthio, heterocyclyl, heterocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted arylalkyl, optionally substitutedheteroarylalkyl, or a pro-drug moiety; R⁵ is selected from the groupconsisting of hydrogen, nitrile, alkyl, cycloalkyl, heterocyclyl,alkenyl, aryl, alkylaryl, arylalkyl, heteroaryl, heteroarylalkyl, andalkylheteroaryl; R¹² and R¹¹ are each independently selected from thegroup consisting of hydrogen, alkyl, arylalkyl and pro-drug moiety; andR¹³ is from one to three substituents independently selected from thegroup consisting of hydrogen, alkyl, heteroalkyl, halogen, arylalkyl,optionally substituted amino, alkoxyl, alkylsulfonyl, arylsulfonyl,alkylsulfinyl, arylsulfinyl, alkylthio, nitro, C(O)OR⁹ and C(O)NR⁹R¹⁰where R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, alkyl, substituted alkyl, heteroalkyl, andarylalkyl.

In another illustrative embodiment, the compounds of the followingformula are described:

In another illustrative embodiment, the compounds of the followingformula are described:

wherein Ar in an optionally substituted aryl group, Ph, alkoxyphenyl,including p, m, and o-anisole, 3,4-benzodioxan, 3,4-benzodioxolan, andthe like;

R¹═NH₂, alkoxy, CH₂OH, and the like;

R²═H, CH₂CHMe₂, (CH2)₂CHMe₂, and the like; and

R═OH, OR⁸, NHR⁸, wherein R⁸ in each occurrence is independently selectedfrom hydrogen, alkyl, including methyl and ethyl, and optionallysubstituted arylalkyl including benzyl, or one or more R⁸ is a pro-drugmoiety.

In another illustrative embodiment, the compounds of the followingformula are described:

wherein R═OH, OR⁸, NHR⁸, wherein R⁸ in each occurrence is independentlyselected from hydrogen, alkyl, including methyl and ethyl, andoptionally substituted arylalkyl including benzyl, or one or more R⁸ isa pro-drug moiety.

It is also appreciated that in the foregoing embodiments, certainaspects of the compounds are presented in the alternative, such asselections for any one or more of R, X¹, X², R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², n, m, and p. It is therefore to be understoodthat various alternate embodiments of the invention include individualmembers of those lists, as well as the various subsets of those lists.Each of those combinations is to be understood to be described herein byway of the lists.

In one embodiment, the following illustrative method for preparingcompounds described herein is as follows:

as described by Ghosh et al. It is to be understood that the abovesynthetic method is adaptable to prepare the entire range of compoundsdescribed herein by the appropriate selection of the correspondingstarting material, or protected variation thereof.

It is to be understood that in each illustrative embodiment describedherein that includes one or more compounds having chiral centers, allpossible diastereomers and enantiomers are described by the structuresboth collectively as various mixtures, including racemic mixtures, aswell as individually as optically active compounds. Wherestereochemistry is indicated in illustrative structures, it is to beunderstood that the indicated stereochemistry is relative and thereforerefers only to those selected diastereomers. In addition, in some casescompounds showing relative chemistry refer both the racemic mixtures aswell as optically enriched or optically pure enantiomers. As describedherein, the preparations, processes, and syntheses for preparing suchcompounds may he performed using optically enriched or optically purestarting materials, or in the alternative reaction conditions that allowfor the asymmetric induction of certain chiral centers.

In another embodiment, compounds of the present invention can heprepared and administered in a wide variety of oral, parenteral andtopical dosage forms. Thus, the compounds of the present invention canhe administered by injection (e.g. intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, orintraperitoneally). Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally. Itis also envisioned that multiple routes of administration (e.g.,intramuscular, oral, transdermal) can be used to administer thecompounds of the invention. Accordingly, the present invention alsoprovides pharmaceutical compositions comprising a pharmaceuticallyacceptable carrier or excipient and one or more compounds of theinvention.

In another embodiment, compounds of the present invention can beprepared and administered in a wide variety of oral, parenteral andtopical dosage forms. Thus, the compounds of the present invention canbe administered by injection (e.g. intravenously, intramuscularly,intracutaneously, subcutaneously, intraduodenally, orintraperitoneally). Also, the compounds described herein can beadministered by inhalation, for example, intranasally. Additionally, thecompounds of the present invention can be administered transdermally. Itis also envisioned that multiple routes of administration (e.g.,intramuscular, oral, transdermal) can be used to administer thecompounds of the invention. Accordingly, the present invention alsoprovides pharmaceutical compositions comprising a pharmaceuticallyacceptable carrier or excipient and one or more compounds of theinvention.

For the treatment of HIV, AIDS, and AIDS-related diseases,illustratively the compounds described herein may be formulated in atherapeutically effective amount in conventional dosage forms, includingone or more carriers, diluents, and/or excipients. Such formulationcompositions may be administered by a wide variety of conventionalroutes in a wide variety of dosage formats, utilizing art-recognizedproducts. See generally, Remington's Pharmaceutical Sciences, (16th ed.1980). It is to be understood that the compositions described herein maybe prepared from isolated compounds described herein or from salts,solutions, hydrates, solvates, and other forms of the compoundsdescribed herein. It is also to be understood that the compositions maybe prepared from various amorphous, non-amorphous, partiallycrystalline, crystalline, and/or other morphological forms of thecompounds described herein.

In making the formulations of the compounds described herein, atherapeutically effective amount of the HIV protease inhibitor, in anyof the various forms described herein, may be mixed with an excipient,diluted by an excipient, or enclosed within such a carrier which can bein the form of a capsule, sachet, paper, or other container. Excipientsmay serve as a diluent, and can be solid, semi-solid, or liquidmaterials, which act as a vehicle, carrier or medium for the activeingredient. Thus, the formulation compositions can be in the form oftablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders. The compositions may contain anywhere from about 0.1% to about99.9% active ingredients, depending upon the selected dose and dosageform. Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions can be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures known in the art. It is appreciated thatthe carriers, diluents, and excipients used to prepare the compositionsdescribed herein are advantageously GRAS (Generally Regarded as Safe)compounds.

The unitary daily dosage of the compounds described in the invention canvary significantly depending on the host condition, the disease statebeing treated, the molecular weight of the conjugate, its route ofadministration and tissue distribution, and the possibility of co-usageof other therapeutic treatments such as radiation therapy. The effectiveamount to be administered to a patient is based on body surface area,patient weight, and physician assessment of patient condition. Aneffective dose can range from about 1 ng/kg to about 50 mg/kg, fromabout 10 ng/kg to about 10 mg/kg, from about 0.10 μg/kg to about 10mg/kg, from about 1 μg/kg to about 5 mg/kg, and from about 10 μg/kg toabout 5 mg/kg.

Any effective regimen for administering the composition comprising acompound of the invention can be used. For example, the compositioncomprising a compound of the invention can be administered as singledoses, or it can be divided and administered as a multiple-dose dailyregimen. Further, a staggered regimen, for example, one to three daysper week can be used as an alternative to daily treatment, and for thepurpose of defining this invention such intermittent or staggered dailyregimen is considered to be equivalent to every day treatment and withinthe scope of this invention.

The compounds described herein may contain one or more chiral centers,or may otherwise be capable of existing as multiple stereoisomers.Accordingly, it is to be understood that the present invention includespure stereoisomers as well as mixtures of stereoisomers, such asenantiomers, diastereomers, and enantiomerically or diastereomericallyenriched mixtures. The compounds described herein may be capable ofexisting as geometric isomers. Accordingly, it is to be understood thatthe present invention includes pure geometric isomers or mixtures ofgeometric isomers.

It is appreciated that the compounds described herein may exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present invention. The compounds ofthe present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Additional features of the present invention will become apparent tothose skilled in the art upon consideration of the following descriptionof illustrative embodiments for carrying out the invention.

EXAMPLES

General. All melting points were recorded on a Thomas-Hoover meltingpoint apparatus and are uncorrected. ¹H NMR and ¹³C NMR spectra wererecorded on Varian Mercury-Vx-300, Bruker Avance 400, Bruker AV-500,Bruker Avance DRX-500 spectrometers. IR spectra were recorded on aMattson Genesis II FT-IR spectrometer. Optical rotations were recordedon a Perkin-Elmer 341 or an Autopol III automeric polarimeter. Anhydroussolvents were obtained as follow: THF and diethyl ether by distillationfrom sodium and benzophenone; pyridine, dichloromethane from CaH₂. Allother solvents were reagent grade. All moisture sensitive reactions werecarried out in a flame dried flask under nitrogen atmosphere. Columnchromatography was performed with Whatman 240-400 mesh silica gel underlow pressure of 3-5 psi. TLC was carried out with E. Merck silica gel60-F-254 plates. Ethyl α-N-tosyl iminoacetate was prepared from ethylglyoxylate and N-toluenesulfonylisocyanate (Sigma-Aldrich) by Weinreb'sprocedure (Tschaen, D. H.; Turos, E.; Weinreb, S. M. J. Org. Chem. 1984,49, 5058).

Example 1

(±)(R)-Ethyl 2-((R)-tetrahydrofuran-3-yl)-2-(tosylamino)acetate (3). Toa mixture of freshly distilled ethyl α-N-tosyl iminoacetate, (1), (255mg, 1.0 mmol) and 2,3-dihydrofuran (84.2 mg, 1.2 mmol) in dry CH₂Cl₂(6.0 mL) at −78° C. was added a solution of TiCl₄ (1.0 M in CH₂Cl₂, 1.2mmol) and the resulting yellow solution containing some precipitate werestirred at −78° C. for an hour. Triethylsilane (581.4 mg, 5.0 mmol) wasadded to the mixture at −78° C. and the mixture was continuously stirredat −78° C. for 2.0 hours. Saturated sodium bicarbonate solution (15 mL)was used to quench the reaction at −78° C. The mixture was allowed towarm to room temperature and the aqueous layer was extracted with ethylacetate (3×15 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure. The residue was furtherpurified by flash column chromatography on silica gel to afford theα-N-tosylamino ester (3) (232.7 mg, 71% yield) as a white solid,Mp=104-105° C.; R_(f)=0.29 (40% EtOAc in hexane). ¹H NMR (500 MHz,CDCl₃): δ 1.07 (t, J=7.2 Hz, 3H), 1.84 (m, 1H), 1.97 (m, 1H), 2.41 (s,3H), 2.49 (m, 1H), 3.64 (m, 1H), 3.72 (m, 2H), 3.78 (m 1H), 3.87 (m,1H), 3.88 (q, J=7.2 Hz, 2H), 5.22 (d, J=7.0 Hz, 1H), 7.35 (d, J=8.3 Hz,2H), 7.70 (d, J=8.3 Hz, 2H); ¹³C NMR (125 MHz, CDCl₃) δ 14.3, 21.9,28.9, 42.9, 57.4, 62.2, 68.1, 69.7, 127.7, 130.1, 136.9, 144.2, 171.4.IR (film, NaCl), 559.1, 667.8, 816.1, 916.6, 1092.0, 1163.5, 1338.9,1457.3, 1738.4, 2825.0 cm; ⁻¹ m/z (ESI) 328.1 (M+H)⁺.

Example 2

(±) (R)-Ethyl2-((2R,3R)-2-allyl-tetrahydrofuran-3-yl)-2-(tosylamino)acetate (5a) and(±) (R)-ethyl2-((2S,3R)-2-allyl-tetrahydrofuran-3-yl)-2-(tosylamino)acetate (6a). Toa mixture of freshly distilled α-N-tosyl imino ester 1 (255 mg, 1.0mmol) and 2,3-dihydrofuran (90.7 mg, 1.2 mmol) in dry CH₂Cl₂ (6.0 mL) at−78° C. was added a solution of TiCl₄ (1.0 M in CH₂Cl₂, 1.2 mmol) andthe resulting yellow solution containing some precipitate were stirredat −78° C. for an hour. Allyltrimethylsilane (229 mg, 2.00 mmol) wasadded to the mixture at −78° C. and mixture was continuously stirred at−78° C. for 2 hours. Saturated sodium bicarbonate solution (15 mL) wasused to quench the reaction at −78° C. The mixture was allowed to warmto room temperature and the aqueous layer was extracted with ethylacetate (3×15 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure. The residue was furtherpurified by flash column chromatography on silica gel to afford theα-N-tosylamino ester 5a (219 mg, 59% yield) and 6a (72.0 mg, 20% yield).Major isomer (±) (R)-ethyl2-((2R,3R)-2-allyl-tetrahydrofuran-3-yl)-2-(tosylamino)acetate (5a):white crystals, Mp=62-64° C.; R_(f)=0.24 (30% EtOAc in hexane). ¹H NMR(500 MHz, CDCl₃): δ 1.06 (t, J=7.2 Hz, 3H), 1.82 (m, 2H), 2.21 (m, 3H),2.40 (s, 3H), 3.85-3.72 (m, 4H), 3.90 (q, J=7.2 Hz, 2H), 5.08 (m, 2H),5.39 (d, J=10.2 Hz, 1H), 5.77 (m, 1H), 7.28 (d, J=8.1 Hz, 2H), 7.69 (d,J=8.1 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃), δ 13.9, 21.5, 27.7, 38.4, 46.1,56.0, 61.9, 66.7, 79.0, 117.4, 127.4, 129.7, 134.3, 136.4, 143.9, 170.9;FT-IR (film, NaCl), 668.9, 916.8, 1091.4, 1162.8, 1265.0, 1445.3,1738.3.2923.2, 2974.2 cm⁻¹; m/z (ESI) 390.2 (M⁺+Na); HRMS (ESI), Calcdfor C₁₈H₂₅NO₅S m/z 390.1351 (M+Na)⁺. found m/z 390.1343 (M+Na)⁺. Minorisomer (±) (R)-ethyl2-((2S,3R)-2-allyl-tetrahydrofuran-3-yl)-2-(tosylamino)acetate (6a): waxsolid; R_(f)=0.20 (30% EtOAc in hexane); ¹H NMR (300 MHz, CDCl₃) δ 1.12(t, J=7.2 Hz, 3H), 2.04 (m, 2H), 2.23 (m, 2H), 2.42 (s, 3H), 2.48 (m,1H), 3.79 (m, 2H), 3.95 (m, 4H), 5.04 (m, 2H), 5.20 (d, J=7.8 Hz, 1H),5.78 (m, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.73 (d, J=8.1 Hz, 2H); ¹³C NMR(75 MHz, CDCl₃), δ 13.9, 21.5, 27.4, 33.7, 44.2, 55.7, 61.7, 66.0, 79.6,117.0, 126.5, 127.4, 129.6, 134.8, 136.1, 143.8, 171.1; FT-IR (film,NaCl), 665.3, 814.7, 1091.2, 1162.5, 1338.3, 1446.2, 1738.3 cm⁻¹; m/z(ESI) 366.5 (M−H)⁻.

Example 3

(±) (R)-Ethyl2-((2R,3R)-2-cyano-tetrahydrofuran-3-yl)-2-(tosylamino)acetate (5b). Toa mixture of freshly distilled α-N-tosyl imino ester (1) (153 mg, 0.60mmol) and 2,3-dihydrofuran (50.5 mg, 0.72 mmol) in dry CH₂Cl₂ (4.0 mL)at −78° C. was added a solution of TiCl₄ (1.0 M in CH₂Cl₂, 0.60 mmol)and the resulting yellow solution containing some precipitate werestirred at −78° C. for an hour. Trimethylsilyl cyanide (119 mg, 1.20mmol) was added to the mixture at −78° C. and mixture was continuouslystirred at −78° C. for 0.5 hour. The mixture was allowed to warm to 0°C. and stirred at 0° C. for 5.0 hours. Saturated sodium bicarbonatesolution (10 mL) was used to quench the reaction at 0° C. The aqueouslayer was extracted with ethyl acetate (3×10 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressure.The residue was further purified by flash column chromatography onsilica gel to afford (5b) (112.3 mg, 64% yield) as a yellow solid,Mp=105-107° C., Rf=0.34 (45% EtOAc in hexane); ¹H NMR (400 MHz, CDCl₃):δ 1.06 (t, J=7.1 Hz, 3H), 1.89 (m, 1H), 2.06 (m, 1H), 2.40 (s, 3H), 2.88(m, 1H), 4.81-3.81 (m, 5H), 4.70 (d, J=5.7 Hz, 1H), 5.74 (d, J=9.4 Hz,1H), 7.28 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H); ¹³C NMR (100 MHz,CDCl₃) δ 13.8 (CH₃), 21.5 (CH₃), 27.6 (CH₂), 48.2 (CH), 55.5 (CH), 62.4(CH₂), 67.9 (CH), 69.0 (CH₂), 118.4 (CN), 127.3 (CH), 129.8 (CH), 135.9(C), 144.3 (C), 169.5 (CO); IR (film, NaCl), 578.2, 666.8, 815.4, 918.5,1091.6, 1164.0, 1305.1, 1339.5, 1447.8, 1738.6, 2255.6, 2983.1 cm⁻¹; m/z(ESI) 375.2 (M⁺+Na).

Example 4

(±) (S)-Ethyl 2-((S)-tetrahydro-2H-pyran-3-yl)-2-(tosylamino)acetate(8). The procedure described for (3) was used for (8). α-N-tosyl iminoester (1) (255 mg, 1.0 mmol), 3,4-dihydro-2H-pyran (101 mg, 1.20 mmol),TiCl₄ (1M in CH₂Cl₂, 1.20 mmol) and triethylsilane (581.4 mg, 5.00 mmol)to afford (8) (334 mg, 98% yield) as a white solid, Mp=102.2-103.8° C.,R_(f)=0.41 (50% EtOAc in hexane); ¹H NMR (400 MHz, CDCl₃): δ 1.06 (3H,t, J=7.1 Hz), 1.41 (ddd, J=23.4, 11.2, 4.1 Hz, 1H), 1.72-1.51 (m, 4H),1.93 (m, 1H), 2.04 (s, 3H), 3.38-3.32 (m, 2H), 3.92-3.74 (m, 3H), 3.88(q, J=7.1 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.2 Hz, 2H); ¹³CNMR (100 MHz, CDCl₃) δ 13.9, 21.5, 24.6, 25.0, 38.8, 57.1, 61.8, 68.2,69.8, 127.4, 129.6, 136.3, 143.8, 170.7; IR (film, NaCl) 559.3, 666.8,1090.0, 1162.9, 1340.1, 1738.5, 2720.9, 2748.1, 2787.0 cm⁻¹; m/z (ESI)342.1 (M+H)⁺.

Example 5

(±)(S)-Ethyl2-((2S,3S)-2-allyl-tetrahydro-2H-pyran-3-yl)-2-(tosylamino)acetate (9a)and (±)(S)-ethyl2-((2R,3S)-2-allyl-tetrahydro-2H-pyran-3-yl)-2-(tosylamino)acetate(10a). The procedure described for (5a) and (6a) was used for (9a) and(10a). α-N-tosyl imino ester (1) (128 mg, 0.50 mmol),3,4-dihydro-2H-pyran (168 mg, 1.0 mmol), TiCl₄ (1M in CH₂Cl₂, 0.60 mmol)and allyltrimethylsilane (115 mg, 1.00 mmol) to afford unseparablemixture of (9a) and (10a) (178.5 mg, 94% yield) as a white solid,Mp=88-91° C., R_(f)=0.43 (50% EtOAc in hexane); ¹H NMR (400 MHz, CDCl₃):δ 1.00 (t, J=7.1 Hz, 3H, major), 1.07 (t, J=7.1 Hz, 3H, minor), 1.34 (m,2H), 1.76 (m, 2H), 1.97 (m, 1H), 2.29 (m, 1H), 2.37 (s, 3H), 2.55 (s,1H), 3.28 (m, 1H, major), 3.43 (m, 1H, major), 3.48 (m, 1H, minor), 3.54(m, 1H, minor), 3.88 (m, 3H), 4.03 (d, J=8.8 Hz, 1H), 4.97 (m, 2H,minor), 5.08 (m, 2H, major), 5.24 (s, 1H), 5.68 (m, 1H, minor), 5.86 (m,1H, major), 7.27 (d, J=7.9 Hz, 2H), 7.69 (d, J=7.9 Hz, 2H, major), 7.73(d, J=7.9 Hz, 2H, minor); ¹³C NMR (100 MHz, CDCl3) δ 13.8, 21.5, 23.3,25.7, 33.2 (minor), 36.7 (major), 39.2 (minor), 41.6 (major), 55.9(major), 56.7 (minor), 61.5 (minor), 61.8 (major), 65.2 (minor), 67.8(major), 76.8, 117.0, 127.4, 129.6, 134.5, 136.1 (major), 136.8 (minor),143.7 (minor), 143.8 (major), 170.5 (major), 171.3 (minor); IR (film,NaCl), 668.0, 815.4, 1089.22, 1163.24, 1340.1, 1738.1, 2931.1 cm⁻¹, m/z(ESI) 382.1 (M⁺+H), 404.2 (M⁺+Na).

Example 6

(±)(S)-ethyl2-((2R,3S)-2-cyano-tetrahydro-2H-pyran-3-yl)-2-(tosylamino)acetate (9b)and (±)(S)-ethyl2-((2S,3S)-2-cyano-tetrahydro-2H-pyran-3-yl)-2-(tosylamino)acetate(10b). The procedure described for 5b was used for 9b and 10b. α-N-tosylimino ester 1 (153 mg, 0.600 mmol), 3,4-dihydro-2H-pyran (60.6 mg, 0.720mmol), TiCl₄ (1 M in CH₂Cl₂, 0.720 mmol) and trimethylsilyl cyanide (119mg, 1.20 mmol) to afford unseparable mixture of 9b and 10b (180.9 mg,99% yield) as a yellow solid, Mp=107-110° C., R_(f)=0.42 (45% EtOAc inhexane); ¹H NMR (400 MHz, CDCl₃): δ 1.048 (t, J=7.1 Hz, 3H, major),1.054 (t, J=7.1 Hz, minor), 1.63-1.54 (br, 4H), 2.04 (br, 1H, minor),2.19 (br, 1H, major), 2.38 (s, 3H), 3.43 (m, 1H, major), 3.70 (m, 1H,minor), 3.99-3.96 (m, 3H), 4.04 (dd, J=9.1, 3.8 Hz, 1H), 4.36 (d, J=9.3Hz, major), 4.64 (d, J=4.3 Hz), 7.27 (d, J=8.2 Hz, 2H), 7.69 (d, J=8.2Hz, 2H, minor), 7.72 (d, J=8.2 Hz, 2H, major); ¹³C NMR (100 MHz, CDCl₃)δ 13.7 (CH₃, minor), 13.8 (CH₃, minor), 21.5 (CH₃), 21.7 (CH₂, major),23.0 (CH₂, minor), 23.5 (CH₂, major), 24.7 (CH₂, minor), 41.4 (CH,minor), 41.6 (CH, major), 55.5 (CH, major), 57.1 (minor), 62.3 (CH₂,minor), 62.6 (CH₂, major), 64.6 (CH₂, minor), 66.7 (CH, minor), 67.5(CH, major), 67.6 (CH₂, major), 115.3 (CN, minor), 117.1 (CN, major),127.3 (CH, minor), 127.5 (CH, major), 129.7 (CH, minor), 129.8 (CH,major), 135.4 (C, major), 136.3 (C, minor), 169.6 (CO, major), 169.7(CO, minor); IR (film, NaCl), 548.2, 668.3, 815.3, 919.6, 1021.0,1089.0, 1164.17, 1341.10, 1447.3, 1735.2, 2255.0, 2339.7, 2360.8,2866.5, 2935.6 cm⁻¹; m/z (ESI) 367.3 (M⁺+H), 389.2 (M⁺+Na).

Example 7

(R)-ethyl2-((3R,5R)-tetrahydro-5-phenylfuran-3-yl)-2-(tosylamino)acetate (13). Toa mixture of freshly distilled α-N-tosyl imino ester (1) (76.6 mg, 0.300mmol) and (R)-2,3-dihydro-2-phenylfuran (11) (52.6 mg, 0.360 mmol) indry CH₂Cl₂ (3.0 mL) at −78° C. was added a solution of TiCl₄ (1.0 M inCH₂Cl₂, 0.36 mmol) and the resulting orange solution were stirred at−78° C. for 50 mins. Dry acetonitrile (61.6 mg, 1.50 mmol) was added at−78° C. and the mixture was stirred at −78° C. for 10 mins.Triethylsilane (174.4 mg, 1.50 mmol) was added and the mixture wasstirred at −78° C. for an hour. Then the mixture was warmed to −20° C.and stirred at −20° C. for two hours. Then the mixture was retooled to−30° C. and quenched carefully with 10 mL ice-chilled saturated sodiumbicarbonate solution. After the mixture was warmed to room temperature,the aqueous layer was extracted with dichloromethane (3×15 mL). Thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure. The residue was further purified by flash columnchromatography on silica gel to afford the α-N-tosylamino ester (13)(84.7 mg, 70% yield) as clear crystals, Mp=97-99° C., R_(f)=0.41(hex:EtOAc=1:1), [α]²³ _(D)=−17.9° (c 1.03, CHCl₃); ¹H NMR (400 MHz,CDCl₃): δ 1.06 (t, J=7.3 Hz, 3H), 1.96 (m, 1H), 2.33 (m, 1H), 2.42 (s,3H), 2.59 (m, 1H), 3.94-3.76 (m, 4H), 4.09 (dd, J=9.1, 7.3 Hz, 1H), 4.99(t, J=7.0 Hz, 1H), 5.28 (d, J=9.9 Hz, 1H), 7.31 (m, 71-1), 7.72 (d,J=6.7 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.9 (CH₃), 21.5 (CH₃), 36.7(CH₂), 42.3 (CH), 56.7 (CH), 62.0 (CH₂), 69.8 (CH₂), 79.8 (CH), 125.4(CH), 127.4 (CH), 128.4 (CH), 129.7 (CH), 136.3 (C), 142.6 (C), 143.9(C), 170.9 (CO); FT-IR (film, NaCl), 562.1, 666.6, 701.4, 1026.3,1163.3, 1339.2, 1494.6, 1599.1, 1736.2, 2872.4, 2981.7 cm⁻¹; m/z (ESI)404.1 (M+H)⁺.

Example 8

(R)-Ethyl2-((2R,3R,5R)-2-cyano-tetrahydro-5-phenylfuran-3-yl)-2-(tosylamino)acetate(14). To a mixture of freshly distilled α-N-tosyl imino ester (1) (76.6mg, 0.300 mmol) and (R)-2,3-dihydro-2-phenylfuran (11) (52.6 mg, 0.360mmol) in dry CH₂Cl₂ (3.0 mL) at −78° C. was added a solution of TiCl₄(1.0 M in CH₂Cl₂, 0.36 mmol) and the resulting orange solution werestirred at −78° C. for an hour. Trimethylsilyl cyanide (59.5 mg, 0.60mmol) was added to the mixture quickly at −78° C. and the mixture wascontinuously stirred at −78° C. for 0.5 hour. Then the mixture wasallowed to warm to −20° C. and stirred at −20° C. for 5.0 hours.Ice-cooled saturated sodium bicarbonate solution (10 mL) was used toquench the reaction carefully at −20° C. The aqueous layer was extractedwith dichloromethane (3×10 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure. The residue wasfurther purified by flash column chromatography on silica gel to afford(14) (80.4 mg, 65% yield) as a yellow oil, R_(f)=0.28 (hex:EtOAc=1:1),[α]²³ _(D)=−17.2° (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ 1.06 (t,J=7.2 Hz, 3H), 2.09 (m, 1H), 2.43 (s, 3H), 2.45 (m, 1H), 2.92 (m, 1H),3.95 (m, 3H), 4.82 (d, J=6.4 Hz, 1H), 5.18 (t, J=6.9 Hz, 1H), 5.54 (d,J=9.4 Hz, 1H), 7.30 (m, 7H), 7.74 (d, J=8.2 Hz, 2H); ¹³C NMR (100 MHz,CDCl₃) δ 13.8 (CH₃), 21.6 (CH₃), 35.7 (CH₂), 47.6 (CH), 55.0 (CH), 62.8(CH₂), 68.3 (CH), 81.8 (CH), 118.1 (CN), 125.4 (CH), 127.4 (CH), 128.0(CH), 129.9 (CH), 135.6 (C), 140.3 (C), 144.4 (C), 169.6 (CO); FT-IR(film, NaCl), 553.7, 668.4, 815.2, 914.5, 1092.2, 1164.0, 1340.1,1449.7, 1494.9, 1598.6, 1738.5, 2249.5 cm⁻¹; m/z (ESI) 427.4 (M−H)⁻.

Example 9

(R)-Ethyl2-((2R,3R,5R)-2-allyl-tetrahydro-5-phenylfuran-3-yl)-2-(tosylamino)acetate(15). To a mixture of freshly distilled α-N-tosyl imino ester (1) (72.2mg, 0.283 mmol) and (R)-2,3-dihydro-2-phenylfuran (11) (50.0 mg, 0.340mmol) in dry CH₂Cl₂ (3.0 mL) at −78° C. was added a solution of TiCl₄(1.0 M in CH₂Cl₂, 0.36 mmol) and the resulting orange solution werestirred at −78° C. for 50 mins. Dry acetonitrile (58.1 mg, 1.42 mmol)was added at −78° C. and the mixture was stirred at −78° C. for 10 mins.Allyltrimethylsilane (65.2 mg, 0.570 mmol) was added and the mixture wasstirred at −78° C. for an hour. Then the mixture was warmed to −20° C.and stirred at −20° C. for two hours. Then the mixture was recooled to−30° C. and the reaction was quenched carefully with 10 mL ice-cooledsaturated sodium bicarbonate solution. After the mixture was warmed toroom temperature, the aqueous layer was extracted with dichloromethane(3×15 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was further purified byflash column chromatography on silica gel to afford the α-N-tosylaminoester (15) (89.1 mg, 71% yield) as a yellow oil, R_(f)=0.38 (40% EtOAcin hexane), [α]²³ _(D)=−9.6° (c 1.0, CHCl₃); ¹H NMR (400 MHz, CDCl₃): δ1.05 (t, J=7.1 Hz, 3H), 1.80 (m, 1H), 2.21 (m, 1H), 2.31 (m, 1H), 2.38(m, 2H), 2.42 (s, 3H), 3.90 (m, 3H), 4.05 (m, 1H), 4.89 (t, J=7.7 Hz,1H), 5.12 (m, 2H), 5.40 (d, J=9.9 Hz, 1H), 5.89 (m, 1H), 7.33-7.23 (m,7H), 7.73 (d, J=8.3 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 13.8 (CH₃), 21.5(CH₃), 36.1 (CH₂), 38.6 (CH₂), 45.9 (CH), 55.9 (CH), 62.0 (CH₂), 79.5(CH), 79.6 (CH), 117.7 (CH₂), 125.7 (CH), 127.4 (CH), 128.3 (CH), 129.7(CH), 134.1 (C), 136.3 (C), 142.1 (C), 144.0 (C), 171.0 (CO); FT-IR(film, NaCl), 545.1, 667.9, 816.2, 1025.4, 1093.9, 1163.2, 1349.2,1746.9, 2980.6 cm⁻¹; m/z (ESI) 444.1 (M+H)⁺, 466.3 (M+Na)⁺.

Example 10

(R)-ethyl2-((3R,5R)-tetrahydro-5-(naphthalen-2-yl)furan-3-yl)-2-(tosylamino)acetate(16). The procedure described for (13) was used for (16). α-N-tosylimino ester (1) (76.6 mg, 0.300 mmol),(R)-2,3-dihydro-2-(naphthalen-2-yl)furan (12) (70.3 mg, 0.360 mmol),TiCl₄ (1M in CH₂Cl₂, 0.360 mmol), acetonitrile (61.6 mg, 1.50 mmol) andtriethylsilane (174 mg, 1.50 mmol) to afford (16) (89.0 mg, 65% yield)as a yellow oil, R_(f)=0.40 (hex:EtOAc=1:1), [α]²³ _(D)=−25.2° (c 1.00,CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 1.07 (t, J=7.2 Hz, 3H), 2.04 (m, 1H),2.40 (m, 1H), 2.41 (s, 3H), 2.64 (m, 1H), 3.87-3.93 (m, 4H), 4.17 (dd,J=9.0, 7.0 Hz, 2H), 5.17 (t, J=7.0 Hz, 1H), 5.31 (d, J=9.5 Hz, 1H), 7.30(d, J=8.0 Hz, 2H), 7.36 (dd, J=8.5, 1.5 Hz, 1H), 7.46 (m, 2H), 7.74 (d,J=8.0 Hz, 3H), 7.81 (d, J=8.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 13.9(CH₃), 21.6 (CH₃), 36.7 (CH₂), 42.4 (CH), 56.8 (CH), 62.0 (CH₂), 70.0(CH₂), 80.0 (CH), 123.7 (CH), 123.9 (CH), 125.8 (CH), 126.2 (CH), 127.4(CH), 127.7 (CH), 127.9 (CH), 128.3 (CH), 129.8 (CH), 132.8 (C), 133.2(C), 136.4 (C), 140.0 (C), 144.0 (C), 171.0 (CO); FT-IR (film, NaCl)550.9, 593.0, 675.2, 737.1, 817.5, 1029.7, 1091.7, 1161.9, 1349.3,1599.0, 1743.8 cm⁻¹; m/z (ESI) 454.1 (M+H)⁺.

Example 11

(R)-ethyl2-((2S,3R,5R)-2-cyano-tetrahydro-5-(naphthalen-2-yl)furan-3-yl)-2-(tosylamino)acetate(17). The procedure described for (5b) was used for (17). α-N-tosylimino ester (1) (76.6 mg, 0.300 mmol),(R)-2,3-dihydro-2-(naphthalen-2-yl)furan (12) (70.3 mg, 0.360 mmol),TiCl₄ (1M in CH₂Cl₂, 0.36 mmol) and trimethylsilyl cyanide (89.3 mg,0.900 mmol) to afford (17) (84.7 mg, 59% yield) as a yellow oil,R_(f)=0.40 (hex: EtOAc=1:1), [α]²³ _(D)=−55.2° (c 1.05, CHCl₃); ¹H NMR(400 MHz, CDCl₃): δ 1.05 (t, J=7.1 Hz, 3H), 2.19 (m, 1H), 2.41 (s, 3H),2.52 (m, 1H), 2.97 (m, 1H), 3.97 (m, 3H), 4.90 (d, J=6.5 Hz, 1H), 5.35(t, J=6.9 Hz, 1H), 5.70 (d, J=5.3 Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 7.39(dd, J=8.6, 1.6 Hz, 1H), 7.48 (m, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.82 (m,4H); ¹³C NMR (100 MHz, CDCl₃) δ 13.8 (CH₃), 21.6 (CH₃), 35.6 (CH₂), 47.5(CH), 55.0 (CH), 62.8 (CH₂), 68.4 (CH), 82.0 (CH), 118.2 (CN), 123.2(CH), 124.4 (CH), 126.2 (CH), 126.4 (CH), 127.4 (CH), 127.7 (CH), 128.1(CH), 128.6 (CH), 129.9 (CH), 133.0 (C), 135.7 (C), 137.6 (C), 144.4(C), 169.6 (CO); FT-IR (film, NaCl), 667.6, 817.2, 1092.0, 1163.7,1446.5, 1738.2, 2820.8, 2922.3 cm⁻¹; m/z (ESI) 477.5 (M

Example 12

(R)-ethyl2-((2R,3R,5R)-2-allyl-tetrahydro-5-(naphthalen-2-yl)furan-3-yl)-2-(tosylamino)acetate(18). The procedure described for (15) was used for (18). α-N-tosylimino ester (1) (76.6 mg, 0.300 mmol),(R)-2,3-dihydro-2-(naphthalen-2-yl)furan (12) (70.6 mg, 0.360 mmol),TiCl₄ (1M in CH₂Cl₂, 0.36 mmol), acetonitrile (61.6 mg, 1.50 mmol) andallyltrimethylsilane (68.6 mg, 0.600 mmol) to afford (18) (104.8 mg, 71%yield) colorless oil, R_(f)=0.48 (Hex: EtOAc=3:2), [α]²³ _(D)=−17.0° (c0.73, CHCl₃); ¹H NMR (500 MHz, CDCl₃): δ 1.06 (t, J=7.0 Hz, 3H), 1.87(m, 1H), 2.29-2.39 (m, 2H), 2.42 (s, 3H), 2.48 (m, 2H), 3.87-3.97 (m,3H), 4.13 (q, J=6.0 Hz, 1H), 5.07 (t, J=7.5 Hz, 1H), 5.14-5.21 (m, 2H),5.41 (d, J=10.0 Hz, 1H), 5.92-5.98 (m, 1H), 7.31 (d, J=8.5 Hz, 2H), 7.40(dd, J=8.5, 1.5 Hz, 1H), 7.46 (m, 2H), 7.74-7.82 (m, 6H); ¹³C NMR (125MHz, CDCl₃) δ 13.9 (CH₃), 21.6 (CH₃), 36.0 (CH₂), 38.7 (CH₂), 46.0 (CH),56.0 (CH), 62.0 (CH₂), 79.6 (CH), 79.9 (CH), 117.8 (CH₂), 123.9 (CH),124.4 (CH), 125.8 (CH), 126.1 (CH), 127.5 (CH), 127.7 (CH), 128.0 (CH),128.2 (CH), 129.8 (CH), 132.9 (C), 133.2 (C), 134.2 (CH), 136.3 (C),139.6 (C), 144.0 (C), 171.0 (CO); FT-IR (film, NaCl) 499.4, 666.2,815.7, 1024.4, 1161.81, 1348.4, 1744.2 cm⁻¹; m/z (ESI) 494.1 (M+H)⁺,516.2 (M+Na)⁺.

Example 13

Deprotection of tosyl group from 5a. (5a) (84.8 mg, 0.231 mmol) wasmixed with 1N LiOH (3.23 mL, 3.23 mmol) and THF (1.15 mL) and wasstirred at room temperature for an hour. Then the solution was adjustedto pH=2 with 1N HCl. The aqueous layer was extracted with ethyl acetate(3×15 mL). The combined organic extracts were dried over anhydrousNa₂SO₄ and the solvent was removed in vacuum. The crude product was usedfor the next reaction without purification. Thus, to a flask equippedwith a condenser were added the crude product from last step, sodiumphosphate dibasic (179.4 mg, 1.26 mmol), methanol (5.0 mL) and 3% Na/Hg(2.95 g, 3.83 mmol). The mixture was refluxed for one day. Then sodiumphosphate dibasic (179.4 mg, 1.26 mmol) and 3% Na/Hg (2.95 g, 3.83 mmol)were added. The mixture was refluxed for another day. Water (2.0 ml) wasused to quench the reaction. Mercury was removed and washed withmethanol. The solution was concentrated. The resulting solid wasdissolved in 10 mL methanol and sodium phosphate dibasic was removed byfiltration. After removing the solvent from the filtrate, the crudeproduct was further purified by column chromatography on silica gel(eluent:CHCl₃:CH₃OH:aqueous ammonia=5:3:1) to afford the desired product(7a) (41.8 mg, 98% yield, two steps) as a white solid, R_(f)=0.36(CHCl₃:CH₃OH:aqueous ammonia=5:3:1). NMR (500 MHz, CD₃OD): δ 1.86 (ddd,J 15.0, 12.5, 7.5 Hz, 1H), 2.08 (m, 1H), 2.25 (dt, J=14.5, 7.5 Hz, 1H),2.40 (m, 1H), 2.45 (in, 1H), 3.54 (d, J=6.0 Hz), 3.81 (m, 2H), 3.97 (dt,J=11.0, 3.5 Hz, 1H), 5.06 (dt, J=10.5, 1.0 Hz, 1H), 5.13 (dd, J=15.5,2.0 Hz, 1H), 5.86 (m, 1H); ¹³C NMR (125 MHz, CD₃OD), δ 28.0 (CH₂), 38.2(CH₂), 44.6 (CH), 56.5 (CH), 66.0 (CH₂), 79.7 (CH), 116.5 (CH₂), 134.4(CH), 171.9 (CO); FT-IR (film, NaCl), 575.4, 687.1, 1365.1, 1404.1,1512.8, 1639.3 cm⁻¹; HRMS (ESI), Calcd for C₉H₁₅NO₃: m/z 186.1130(M+H)⁺. found m/z 186.1127 (M+H)⁺.

Example 14

Determination of Diastereomeric Ratios. The chiral products (13)-(18)was reduced to primary alcohol with LiAlH₄ in ethyl ether at 0° C., thenthe crude product was coupled with (R)-Mosher acid using EDCI and DMAP.The coupling product was purified by flash chromatography and the ¹⁹FNMR spectra of the desired Mosher ester was taken to determine the de %with integration (Lee, J.; Kobayashi, Y.; Tezuka, K.; and Kishi Y. Org.Lett., 1999, 1, 2181-84).

TABLE 1 Inhibition of HIV Protease by compounds of the following formula

K_(i) No. R¹ R² R³ Y (nM) 1 1-naphthyl allyl H p-MePhSO₂ 0.70 2 Ph H Hp-MePhSO₂ 0.75 3 1-naphthyl H H p-MePhSO₂ 0.72 4 Ph H isoBup-MeOPhSO₂ >1000 5 PhCH₂ ally H p-MePhSO₂ 0.41 6 PhCH₂ H H p-MePhSO₂0.28 7 PhCH₂ H isoBu p-MePhSO₂ 19 8 m-MeOPh H H p-MePhSO₂ >1000 91-naphthyl allyl H p-MeOPhSO₂ 51 10 PhCH₂ H H p-MeOPhSO₂ 1.4 11p-MeOPhCH₂ H H p-MePhSO₂ >10 12 p-MeOPhCH₂ allyl H p-MePhSO₂ 84 13 PhCH₂H H p-MePhSO₂ 200 14 p-HOCH₂PhCH₂ H H p-MePhSO₂ 480 15 p-HOCH₂PhCH₂allyl H p-MePhSO₂ 370 16 PhCH₂ H H p- >1000 HOCH₂PhSO₂ 17 Ph allyl Hbenzamide >1000 18 Ph allyl H p-FPhSO₂ >1000 19 Ph 2-N-benzylaminoethylH p-MePhSO₂ 3 20 Ph 2-HO-2-Ph-ethyl H p-MePhSO₂ 670 single isomer 21 Ph2-HO-2-Ph-ethyl H p-MePhSO₂ 4 diastereomeric mixture 22 Ph2,3-dihydroxypropyl H p-MePhSO₂ 27 23 Ph

H p-MePhSO₂ >1000 24 Ph

H p-MePhSO₂ 500 25 Ph allyl H p-MePhSO₂ >1000 26 2-naphthyl2-HO-2-Ph-ethyl H p-MePhSO₂ 150 single isomer, lower Rf 27 2-naphthyl2-HO-2-Ph-ethyl H p-MePhSO₂ 480 single isomer, higher Rf 28 Ph allyl H

>1000 29 Ph 2-OH-3-N-morpholino- H p-MePhSO₂ >1000 propyl 30 PhN-benzylaminomethyl H p-MePhSO₂ >1000 31 Ph

H p-MePhSO₂ >1000 32 Ph

H p-MePhSO₂ 500 33 Ph 1-E-propenyl H p-MePhSO₂ >1000 34 2-naphthyl allylH p-MePhSO₂ 1000 35 p-methoxymethyl- allyl H p-MePhSO₂ >1000 Ph

TABLE 2 Inhibition of HIV Protease No. Compound K_(i) (nM) 1

95 2

>1000 3

32

What is claimed is:
 1. A pharmaceutical composition comprising compoundof the formula:

Wherein: R¹ is optionally substituted alkyl or aryl; R² is hydrogen oroptionally substituted alkyl; R⁵ is hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, or nitrile; R⁷ is hydrogen; R⁸ isoptionally substituted arylalkyl; and R¹¹ is hydrogen, alkyl, arylalkyl,or a pro-drug moiety; and one or more carriers, diluents or excipients,and combinations thereof.
 2. The pharmaceutical composition of claim 1,wherein R¹ is optionally substituted aryl.
 3. The pharmaceuticalcomposition of claim 2, wherein the aryl is phenyl.
 4. Thepharmaceutical composition of claim 2, wherein the aryl is substitutedwith alkyl, alkoxy, nitro, amino, or alkoxyalkyl.
 5. The pharmaceuticalcomposition of claim 1, wherein R⁸ is aryl optionally substituted withhydroxyl, alkoxy or hydroxyalkyl.
 6. The pharmaceutical composition ofclaim 1, wherein R⁵ is arylalkyl, alkoxyalkyl, or aminoalkyl.
 7. Amethod for treating a patient in need of relief from HIV, AIDS, or anAIDS-related disease, the method comprising the step of administering tothe patient a therapeutically effective amount of the pharmaceuticalcomposition of claim 1.